The prefrontal cortex (PFC) integrates inputs from many cortical and subcortical areas to guide decision making and executive control. Two important afferent pathways—from the hippocampus and the contralateral PFC—extend through all PFC layers, but what neurons the afferents target and how the targets process and integrate the transmitted information are poorly understood. Answering these questions is difficult, because EPSPs evoked by synaptic inputs to pyramidal neurons' distal apical dendrites are greatly attenuated by the time they reach the soma, where electrophysiological recordings are typically made. Nevertheless, such inputs likely influence neuronal outputs by eliciting dendritic spikes and/or integrating with other synaptic inputs. Further complicating the quest to understand cortical information processing, cortical layer 5 (L5) houses two classes of pyramidal neurons: pyramidal tract (PT) neurons, which project to the thalamus, basal ganglia, brainstem, and spinal cord; and intratelencephalic (IT) neurons, which are the only cortical neurons to project to the contralateral hemisphere. These neurons differ not only in their projection patterns, but also in their gene expression profiles and intrinsic electrophysiological properties. Thus, these two neuron classes may process afferent input in different ways.

Trains of simulated synaptic current (bottom) injected into the apical dendrite of L5 pyramidal neurons produced EPSPs in the dendrite (middle) that traveled to the soma (top). Summation of EPSPs at the soma was greater in IT neurons (red) than in PT neurons (green). See Dembrow et al. for details.

To clarify how L5 pyramidal cells in rat medial PFC process synaptic input, Dembrow et al. recorded from the soma and apical dendrites of IT and PT neurons while optically stimulating hippocampal or commissural afferents. Both afferent types provided monosynaptic input to both the apical tuft and perisomatic regions of IT and PT neurons, but hippocampal input to the apical tuft of PT neurons was uncommon, occurring in only one of five cells. In addition, although amplitude attenuated similarly as EPSPs traveled from the apical tuft to the soma in IT and PT neurons, the half-width and delay-to-peak at the soma were significantly greater in IT cells. Together, the data suggest that PT and IT neurons respond differently to hippocampal and commissural inputs, and that while PT neurons are driven most effectively by synchronous inputs, IT neurons can integrate information over a broader temporal window. Thus, PFC neurons projecting to different areas may extract different information from afferent input.

Serotonin Increases the Excitability of DCN Principal Neurons

The dorsal cochlear nucleus (DCN) is involved in localizing sounds based on spectral characteristics, and it integrates auditory and somatosensory information—possibly to help animals orient toward salient sounds and/or to filter out auditory effects of the animal's own movements. The DCN is densely innervated by serotonergic fibers, which have been proposed to mediate context-dependent modulation of auditory responses. Serotonin release increases when animals might benefit from being more attentive to sound. For example, it is higher during wakefulness than during sleep, and its levels increase in auditory brain areas during exposure to noise, stress, and social interactions. How DCN neurons respond to serotonin has not previously been elucidated, however.

Tang and Trussell now report that exogenous serotonin, as well as optical activation of serotonergic terminals, caused a slow inward current that increased spontaneous spiking in fusiform neurons—the principal projection neurons of the DCN—in mouse brainstem slices. The serotonin-induced current was reduced by selective antagonists of 5-HT2A, 5-HT2C, and 5-HT7 receptors and was mimicked by 5-HT2A/2C receptor agonists. The effects of serotonin were also blocked by selective blockers of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Additional experiments indicated that HCN channels were partially active in the absence of exogenous serotonin, but serotonin caused the channels to become activated more quickly and at more depolarized membrane potentials. These effects appeared to be mediated by activation of Src kinases and adenylyl cyclase by HT2A/2C and 5-HT7 receptors, respectively.

These data indicate that serotonin increases the excitability of DCN output neurons. The authors speculate that this may increase acoustic responses by lowering the acoustic threshold of fusiform cells. Looking beyond normal DCN function, the data suggest that serotonin may have a role in tinnitus. Tinnitus is associated with increased spontaneous activity in fusiform cells, particularly those tuned to the frequency of the phantom sound. This strongly implicates these neurons in the phantom perception. Although this hyperactivity has been proposed to result from reduced inhibitory input and/or increased excitatory input to fusiform cells, this new work suggests that serotonin can contribute to the phenomenon by modulating the intrinsic electrophysiological properties of fusiform neurons.